US6200599B1ExpiredUtilityPatentIndex 92
Ortho ester lipids
Est. expiryOct 7, 2019(expired)· nominal 20-yr term from priority
A61P 9/12A61P 7/02A61P 3/10A61P 37/00A61P 9/14A61P 9/10A61P 9/04A61P 37/08A61P 5/18A61P 43/00A61P 3/08A61P 3/06A61P 31/10A61P 25/18A61P 35/00A61P 3/14A61P 3/04A61P 25/08A61P 31/12A61P 25/20A61P 29/00A61P 25/22A61P 31/04A61P 29/02A61P 25/36A61P 25/24A61P 1/04A61P 19/02A61P 19/08A61P 21/02A61P 23/02A61K 9/1272C07D 493/08
92
PatentIndex Score
45
Cited by
14
References
28
Claims
Abstract
The present invention provides ortho ester lipids and their derivatives that, upon certain pH conditions, undergo hydrolysis with concomitant or subsequent headgroup cleavage. These ortho ester lipids can advantageously be formulated into liposomes. The liposome formulations are useful in nucleic acid transfection and entrapment/delivery of conventional small molecules and therapeutic agents. Moreover, the liposomes comprising compounds of the present invention are useful as drug delivery vehicles.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1. A compound having the formula
wherein:
R 1 is a member selected from the group consisting of optionally substituted (C 7 -C 17 )alkyl, optionally substituted (C 7 -C 17 )alkenyl and optionally substituted (C 7 -C 17 )alkynyl;
R 2 is a member selected from the group consisting of (C 1 -C 18 )alkoxy and (C 1 -C 18 )alkylthio;
R 3 is hydrogen; alternatively,
R 2 and R 3 and the carbons to which they are bound join to form a 5,6-membered; a 6,6-membered; a 6,7-membered; or a 7,7-membered bicyclic ortho ester or ortho thioester ring;
A and A 1 are members independently selected from the group consisting of oxygen and sulfur;
x and y are independently selected from the integers 0, 1 and 2;
Z is a member selected from the group consisting of optionally substituted alkylene, optionally substituted alkyleneoxyalkylene and optionally substituted alkyleneaminoalkylene;
Q is a member selected from the group consisting of carboxyl, thiocarboxyl, dithiocarboxyl, carbonate, carbamate, phospho, phosphothio, phosphoro and thiophosphoro; and
R 4 is a nitrogen containing headgroup wherein the nitrogen can be unsubstituted, mono-substituted, di-substituted, or a quaternary nitrogen salt and wherein the nitrogen substituent(s) are member(s) independently selected from the group consisting of optionally substituted (C 1 -C 18 )alkyl, optionally substituted (C 1 -C 18 )alkenyl, and optionally substituted (C 1 -C 18 )alkynyl and wherein R 4 and Q are optionally linked with a (C 1 -C 5 )alkylene or (C 2 -C 5 )alkenyl group.
2. The compound of claim 1 , wherein:
R 1 is a member selected from the group consisting of (C 7 -C 17 )alkyl and substituted (C 7 -C 17 )alkyl;
R 2 and R 3 and the carbons to which they are bound join to form a 6,6-membered; a 6,7-membered; or a 7,7-membered bicyclic ortho ester ring;
A and A 1 are oxygen;
x and y are independently selected from the integers 0, 1 and 2;
Z is optionally substituted alkylene;
Q is a member selected from the group consisting of carboxyl, phospho, and phosphoro;
R 4 is a member selected from the group consisting of optionally substituted amino(C 1 -C 5 )alkylene, optionally substituted (C 1 -C 18 )alkylamino(C 1 -C 5 )alkylene, optionally substituted (C 1 -C 18 )alkoylamino(C 2 -C 5 )alkenyl, optionally substituted (C 1 -C 18 )dialkylamino(C 1 -C 5 )alkylene, optionally substituted (C 1 -C 18 )dialkylamino(C 2 -C 5 )alkenyl, and
a quaternary nitrogen salt having the structure
R 5 R 6 R 7 N + —(CH 2 ) n —X −
wherein:
R 5 , R 6 and R 7 are members independently selected from the group consisting of hydrogen, optionally substituted (C 1 -C 18 )alkyl, optionally substituted (C 2 -C 18 )alkenyl and optionally substituted (C 2 -C 18 )alkynyl;
n is an integer from 1 to 5 inclusive; and
X is a member selected from the group consisting of chloride, iodide, fluoride and bromide.
3. The compound of claim 1 , having the formula
wherein:
R 1 is a member selected from the group consisting of (C 7 -C 17 )alkyl and substituted (C 7 -C 17 )alkyl;
Z is optionally substituted alkylene;
Q is carboxyl;
R 4 is a member selected from the group consisting of optionally substituted (C 1 -C 18 )alkylamino(C 1 -C 5 )alkylene, optionally substituted (C 1 -C 18 )dialkylamino(C 1 -C 5 )alkylene and a quaternary nitrogen salt having the structure
R 5 R 6 R 7 N + —(CH 2 ) n —X −
wherein: R 5 , R 6 and R 7 are members independently selected from the group consisting of hydrogen, optionally substituted (C 1 -C 18 )alkyl, optionally substituted (C 2 -C 18 )alkenyl and optionally substituted (C 2 -C 18 )alkynyl;
n is an integer from 1 to 5 inclusive; and
X is a member selected from the group consisting of chloride, iodide, fluoride and bromide.
4. The compound of claim 3 , wherein:
R 1 is (C 7 -C 17 )alkyl optionally substituted with one or more members selected from the group consisting of lower alkyl, acyl, halogen, hydroxy, amino, alkoxy, alkylamino, acylamino, acyloxy, and mercapto;
Z is (C 1 -C 3 ) alkylene optionally substituted with one or more members selected from the group consisting of lower alkyl, aryl, acyl, halogen, hydroxy, amino, alkoxy, alkylamino, acylamino, acyloxy, aryloxy, aryloxyalkyl, mercapto, both saturated and unsaturated cyclic hydrocarbons and heterocycles;
R 4 is a member selected from the group consisting of optionally substituted (C 1 -C 18 )alkylamino(C 1 -C 5 )alkylene or optionally substituted (C 1 -C 18 )dialkylamino(C 1 -C 5 )alkylene, wherein the substituent is one or more members selected from the group consisting of lower alkyl, aryl, acyl, halogen, hydroxy, amino, alkoxy, alkylamino, acylamino, acyloxy, aryloxy, aryloxyalkyl, mercapto, both saturated and unsaturated cyclic hydrocarbons and heterocycles; and an ammonium salt having the structure:
R 5 R 6 R 7 N + —(CH 2 ) n —X −
wherein:
R 5 is methyl;
R 6 and R 7 are members independently selected from the group consisting of hydrogen, optionally substituted (C 1 -C 18 )alkyl and optionally substituted (C 2 -C 18 )alkenyl;
n is 2; and
X is iodide.
5. The compound of claim 4 , wherein:
R 1 is (C 7 -C 17 )alkyl optionally substituted with (C 7 -C 18 )acyloxy;
Z is (C 1 -C 3 ) alkylene optionally substituted with (C 7 -C 18 )alkoxy; and
R 4 is a member selected from the group consisting of optionally substituted (C 1 -C 18 )alkylamino(C 1 -C 5 )alkylene, optionally substituted (C 1 -C 18 )dialkylamino(C 1 -C 5 )alkylene wherein the substituent is (C 1 -C 18 )acyloxy, and an ammonium salt wherein:
R 6 is methyl.
6. The compound of claim 3 , wherein:
R 1 is a (C 13 -C 17 )alkyl;
Z is (C 1 -C 3 )alkylene;
R 4 is a member selected from the group consisting of (C 14 -C 18 )acyloxy(C 1 -C 5 )alkylamino(C 2 -C 4 )alkylene and an ammonium salt wherein:
R 5 and R 6 are both methyl; and
R 7 is (C 14 -C 18 )acyloxy(C 1 -C 5 )alkylene.
7. The compound of claim 3 , wherein:
R 1 is (C 14 )alkyl;
Z is (C 2 )alkylene; and
R 4 is a member selected from the group consisting of (C 14 )alkylamino(C 2 )alkylene and an ammonium salt wherein:
R 5 and R 6 are both methyl; and
R 7 is (C 14 )alkyl.
8. The compound of claim 3 , wherein:
R 1 is (C 14 )alkyl;
Z is (C 2 )alkylene; and
R 4 is a member selected from the group consisting of N-methyl-N-(tetradecanyl)amino(C 2 )alkylene and an ammonium salt thereof wherein:
R 5 and R 6 are both methyl; and
R 7 is (C 14 )alkyl.
9. The compound of claim 5 , wherein:
R 1 is (C 14 )acyloxy(C 13 )alkyl.
10. The compound of claim 5 , wherein:
R 4 is a member selected from the group consisting of (C 15 )acyloxy(C 2 )alkyleneamino(C 2 )alkylene; and an ammonium salt wherein:
R 7 is (C 15 )acyloxy(C 2 )alkylene.
11. The compound of claim 3 , wherein: said compound is N,N-dimethyl-N-tetradecyl-N-(2-[3-(3,5,8-trioxa-4-tridecylbicyclo[2.2.2]octyl)propanoyloxy]ethyl) ammonium iodide.
12. The compound of claim 3 , wherein: said compound is (N,N-dimethyl-N-(2-[3-(3,5,8-trioxa-4-heptylbicyclo[2.2.2]octyl)propanoyloxy]ethyl)-N-(2-tetradecanoyloxy)ethyl ammonium iodide.
13. A lipid formulation comprising a compound of the formula
wherein:
R 1 is a member selected from the group consisting of optionally substituted (C 7 -C 17 )alkyl, optionally substituted (C 7 -C 17 )alkenyl and optionally substituted (C 7 -C 17 )alkynyl;
R 2 is a member selected from the group consisting of (C 1 -C 18 )alkoxy and (C 1 -C 18 )alkylthio;
R 3 is hydrogen; alternatively,
R 2 and R 3 and the carbons to which they are bound join to form a 5,6-membered; a 6,6-membered; a 6,7-membered; or a 7,7-membered bicyclic ortho ester or ortho thioester ring;
A and A 1 are members independently selected from the group consisting of oxygen and sulfur;
x and y are independently selected from the integers 0, 1 and 2;
Z is a member selected from the group consisting of optionally substituted alkylene, optionally substituted alkyleneoxyalkylene and optionally substituted alkyleneaminoalkylene;
Q is a member selected from the group consisting of carboxyl, thiocarboxyl, dithiocarboxyl, carbonate, carbamate, phospho, phosphothio, phosphoro and thiophosphoro; and
R 4 is a nitrogen containing headgroup wherein the nitrogen can be unsubstituted, mono-substituted, di-substituted, or a quaternary nitrogen salt and wherein the nitrogen substituent(s) are member(s) independently selected from the group consisting of optionally substituted (C 1 -C 18 )alkyl, optionally substituted (C 1 -C 18 )alkenyl, and optionally substituted (C 1 -C 18 )alkynyl and wherein R 4 and Q are optionally linked with a (C 1 -C 5 )alkylene or (C 2 -C 5 )alkenyl group; and
a bioactive agent.
14. The lipid formulation of claim 13 , wherein said bioactive agent is a nucleic acid.
15. The lipid formulation of claim 13 , wherein said compound is formulated into a liposome.
16. The lipid formulation of claim 13 , wherein said compound has the formula:
wherein:
R 1 is a member selected from the group consisting of (C 7 -C 17 )alkyl and substituted (C 7 -C 17 )alkyl;
Z is optionally substituted alkylene;
Q is carboxyl;
R 4 is a member selected from the group consisting of optionally substituted (C 1 -C 18 )alkylamino(C 1 -C 5 )alkylene, optionally substituted (C 1 -C 18 )dialkylamino(C 1 -C 5 )alkylene and a quaternary nitrogen salt having the structure
R 5 R 6 R 7 N + —(CH 2 ) n —X −
wherein: R 5 , R 6 and R 7 are members independently selected from the group consisting of hydrogen, optionally substituted (C 1 -C 18 )alkyl, optionally substituted (C 2 -C 18 )alkenyl and optionally substituted (C 2 -C 18 )alkynyl;
n is an integer from 1 to 5 inclusive; and
X is a member selected from the group consisting of chloride, iodide, fluoride and bromide.
17. The lipid formulation of claim 16 , wherein:
R 1 is (C 7 -C 17 )alkyl optionally substituted with one or more members selected from the group consisting of lower alkyl, acyl, halogen, hydroxy, amino, alkoxy, alkylamino, acylamino, acyloxy, and mercapto;
Z is (C 1 -C 3 ) alkylene optionally substituted with one or more members selected from the group consisting of lower alkyl, aryl, acyl, halogen, hydroxy, amino, alkoxy, alkylamino, acylamino, acyloxy, aryloxy, aryloxyalkyl, mercapto, both saturated and unsaturated cyclic hydrocarbons and heterocycles;
R 4 is a member selected from the group consisting of optionally substituted (C 1 -C 18 )alkylamino(C 1 -C 5 )alkylene or optionally substituted (C 1 -C 18 )dialkylamino(C 1 -C 5 )alkylene, wherein the substituent is one or more members selected from the group consisting of lower alkyl, aryl, acyl, halogen, hydroxy, amino, alkoxy, alkylamino, acylamino, acyloxy, aryloxy, aryloxyalkyl, mercapto, both saturated and unsaturated cyclic hydrocarbons and heterocycles; and an ammonium salt having the structure:
R 5 R 6 R 7 N + —(CH 2 ) n —X −
wherein:
R 5 is methyl;
R 6 and R 7 are members independently selected from the group consisting of hydrogen, optionally substituted (C 1 -C 18 )alkyl and optionally substituted (C 2 -C 18 )alkenyl;
n is2;and
X is iodide.
18. The lipid formulation of claim 17 , wherein:
R 1 is (C 7 -C 17 )alkyl optionally substituted with (C 7 -C 18 )acyloxy;
Z is (C 1 -C 3 ) alkylene optionally substituted with (C 7 -C 18 )alkoxy; and
R 4 is a member selected from the group consisting of optionally substituted (C 1 -C 18 )alkylamino(C 1 -C 5 )alkylene, optionally substituted (C 1 -C 18 )dialkylamino(C 1 -C 5 )alkylene wherein the substituent is (C 1 -C 18 )acyloxy, and an ammonium salt wherein:
R 6 is methyl.
19. The lipid formulation of claim 17 , wherein:
R 1 is a (C 14 -C 17 )alkyl;
Z is (C 1 -C 3 )alkylene;
R 4 is a member selected from the group consisting of (C 14 -C 18 )acyloxy(C 1 -C 5 )alkylamino(C 2 -C 4 )alkylene and an ammonium salt wherein:
R 6 is methyl; and
R 7 is (C 14 -C 18 )acyloxy(C 1 -C 5 )alkylene.
20. The lipid formulation of claim 17 , wherein:
R 1 is (C 13 )alkyl;
Z is (C 2 )alkylene; and
R 4 is a member selected from the group consisting of N-methyl-N-(tetradecanyl)amino(C 2 )alkylene and an ammonium salt thereof wherein:
R 6 is methyl; and
R 7 is (C 14 )alkyl.
21. The lipid formulation of claim 17 , wherein:
R 1 is (C 14 )acyloxy(C 13 )alkyl.
22. The lipid formulation of claim 17 , wherein:
R 4 is a member selected from the group consisting of (C 15 )acyloxy(C 2 )alkyleneamino(C 2 )alkylene; and an ammonium salt wherein:
R 7 is (C 15 )acyloxy(C 2 )alkylene.
23. A method for transfecting a cell, said method comprising:
contacting said cell with a lipid formulation comprising a compound of the formula
wherein:
R 1 is a member selected from the group consisting of optionally substituted (C 7 -C 17 )alkyl, optionally substituted (C 7 -C 17 )alkenyl and optionally substituted (C 7 -C 17 )alkynyl;
R 2 is a member selected from the group consisting of (C 1 -C 18 )alkoxy and (C 1 -C 18 )alkylthio;
R 3 is hydrogen; alternatively,
R 2 and R 3 and the carbons to which they are bound join to form a 5,6-membered; a 6,6-membered; a 6,7-membered; or a 7,7-membered bicyclic ortho ester or ortho thioester ring;
A and A 1 are members independently selected from the group consisting of oxygen and sulfur;
x and y are independently selected from the integers 0, 1 and 2;
Z is a member selected from the group consisting of optionally substituted alkylene, optionally substituted alkyleneoxyalkylene and optionally substituted alkyleneaminoalkylene;
Q is a member selected from the group consisting of carboxyl, thiocarboxyl, dithiocarboxyl, carbonate, carbamate, phospho, phosphothio, phosphoro and thiophosphoro; and
R 4 is a nitrogen containing headgroup wherein the nitrogen can be unsubstituted, mono-substituted, di-substituted, or a quaternary nitrogen salt and wherein the nitrogen substituent(s) are member(s) independently selected from the group consisting of optionally substituted (C 1 -C 18 )alkyl, optionally substituted (C 1 -C 18 )alkenyl, and optionally substituted (C 1 -C 18 )alkynyl and wherein R 4 and Q are optionally linked with a (C 1 -C 5 )alkylene or (C 2 -C 5 )alkenyl group; and
a nucleic acid, thereby transfecting said cell.
24. The method of claim 23 , wherein said lipid formulation comprises a liposome.
25. A method for delivering a bioactive agent to a cell, said method comprising:
contacting said cell with a lipid formulation comprising a compound of the formula
wherein:
R 1 is a member selected from the group consisting of optionally substituted (C 7 -C 17 )alkyl, optionally substituted (C 7 -C 17 )alkenyl and optionally substituted (C 7 -C 17 )alkynyl;
R 2 is a member selected from the group consisting of (C 1 -C 18 )alkoxy and (C 1 -C 18 )alkylthio;
R 3 is hydrogen; alternatively,
R 2 and R 3 and the carbons to which they are bound join to form a 5,6-membered; a 6,6-membered; a 6,7-membered; or a 7,7-membered bicyclic ortho ester or ortho thioester ring;
A and A 1 are members independently selected from the group consisting of oxygen and sulfur;
x and y are independently selected from the integers 0, 1 and 2;
Z is a member selected from the group consisting of optionally substituted alkylene, optionally substituted alkyleneoxyalkylene and optionally substituted alkyleneaminoalkylene;
Q is a member selected from the group consisting of carboxyl, thiocarboxyl, dithiocarboxyl, carbonate, carbamate, phospho, phosphothio, phosphoro and thiophosphoro; and
R 4 is a nitrogen containing headgroup wherein the nitrogen can be unsubstituted, mono-substituted, di-substituted, or a quaternary nitrogen salt and wherein the nitrogen substituent(s) are member(s) independently selected from the group consisting of optionally substituted (C 1 -C 18 )alkyl, optionally substituted (C 1 -C 18 )alkenyl, and optionally substituted (C 1 -C 18 )alkynyl and wherein R 4 and Q are optionally linked with a (C 1 -C 5 )alkylene or (C 2 -C 5 )alkenyl group; and a bioactive agent,
thereby delivering said bioactive agent to said cell.
26. The method of claim 25 , wherein said bioactive agent is a member selected from the group consisting of antimicrobials, antibiotics, antimyobacterials, antifungals, antivirals, neoplastic agents, agents affecting the immune response, blood calcium regulators, agents useful in glucose regulation, anticoagulants, antithrombotics, antihyperlipidemic agents, cardiac drugs, thyromimetic drugs, antithyroid drugs, adrenergics, antihypertensive agents, cholinergics, anticholinergics, antispasmodics, antiulcer agents, skeletal and smooth muscle relaxants, prostaglandins, general inhibitors of the allergic response, antihistamines, local anesthetics, analgesics, narcotic antagonists, antitussives, sedative-hypnotic agents, anticonvulsants, antipsychotics, anti-anxiety agents, antidepressant agents, anorexigenics, non-steroidal anti-inflammatory agents, steroidal anti-inflammatory agents, antioxidants, vaso-active agents, bone-active agents, antiarthritics, diagnostic agents, antineoplastic agents and anti-infective agents.
27. The method of claim 25 , wherein said bioactive agent is a small molecule.
28. The method of claim 25 , wherein said lipid formulation is a liposome.Cited by (0)
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